Endothelin-1-mediated cerebral ischemia in mice: early cellular events and the role of caspase-3.

Over the past 30 years a number of animal models of cerebral ischemic injury have been developed. Middle cerebral artery occlusion (MCAO) in particular reproduces both ischemic and reperfusion elements and is widely utilized as a model of ischemic stroke in rodents. However substantial variability exists in this model even in clonal inbred mice due to stochastic elements of the cerebral vasculature. Models such as MCAO thus exhibit significant irreducible variabilities with respect to their zone of injury as well as inducing a sizable volume of injury to the cerebrum with damage to sub-cortical structures, conditions not typically seen for the majority of human clinical strokes. An alternative model utilizes endothelin-1 application focally to cerebral vasculature, resulting in an ischemic reperfusion injury which more closely mimics that seen in human clinical stroke. In order to further define this model we demonstrate that intra-cortical administration of ET-1 results in a highly reproducible pattern of tissue injury which is limited to the cerebral cortex, characterizing the early cellular and molecular events which occur during the first 24 h post-injury. In addition we demonstrate that caspase-3 is both necessary and sufficient to regulate a majority of cortical cell death observed during this period. The enhanced survival effects seen upon genetic deletion of caspase-3 appear to arise as a result of direct modification of cell autonomous PCD signaling as opposed to secondary effectors such as granulocyte infiltration or microglia activation. Taken together these findings detail the early mechanistic features regulating endothelin-1-mediated ischemic injury.

Factors associated with brain volume in major depression in older adults without dementia: results from a large autopsy study.

OBJECTIVE: We examined brain volume and atrophy in individuals with major depressive disorder (MDD) without dementia that were referred to a large autopsy service. We also examined potential risk factors for brain atrophy, including demographics and clinical variables. METHODS: In this study, 1373 participants (787 male) aged 50 years or older who died from natural causes were included. Participants with no reliable informant, with cognitive impairment or dementia, with a medical history of severe chronic disease, or with prolonged agonal state were excluded. Presence of MDD at least once in their lifetime was defined according to the Structured Clinical Interview for DSM. Brain volume was measured immediately after removal from the skull. RESULTS: Mean age at death was 68.6 ± 11.6, and MDD was present in 185 (14%) individuals. Smaller brain volume was associated with older age (p < 0.001), lower education (years; p < 0.001), hypertension (p = 0.001), diabetes (p = 0.006), and female gender (p < 0.001). In the multivariate analysis adjusted for sociodemographics and cardiovascular risk factors, smaller brain volume was not associated with major depression (ß = -0.86, 95% CI = -26.50 to 24.77, p = 0.95). CONCLUSIONS: In this large autopsy study of older adults, MDD was not associated with smaller brain volumes. Regardless of the presence of MDD, in this sample of older adults without dementia, we found that smaller brain volumes were associated with risk factors for brain neurodegeneration such as older age, diabetes, hypertension, and lower education. Copyright © 2017 John Wiley & Sons, Ltd.

Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder.

Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3-nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation [lipid hydroperoxides (LPH), 8-isoprostane (8-Iso), 4-hydroxy-2-nonenal (4-HNE)] were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3-nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8-Iso was found increased in the BD group while 4-HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins. Oxidative stress has been shown to be higher in the brain of patients with bipolar disorder (BD). Here, we demonstrated increased levels of protein oxidation in synaptosomes from postmortem prefrontal cortex from patients from BD group, while 3-nitrotyrosine was increased in mitochondria from BD and schizophrenia (SCZ) groups. Moreover, lipid peroxidation was found increased in the BD when compared with controls; suggesting that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.